TECHNICAL FIELD
[0001] The application relates to organic synthesis, and specifically to a novel method
for preparing 2-(cyclohexenylidene) malonic acid derivatives and uses thereof.
BACKGROUND
[0003] In the first method, a cyclohexenone derivative is used as a starting material for
preparing the 2-(cyclohexenylidene) malonic acid derivative (
J. Mol. Cata. A. Chem. 2003, 195 (1-2), 263). The cyclohexenone derivative reacts with a malonic acid derivative through Knoevenagel
condensation to produce the 2-(cyclohexenylidene) malonic acid derivative. Such method
requires a highly active cyclohexenone. For less active 6-substituted cyclohexenone
starting material, due to large steric hindrance, the yield of the Knoevenagel condensation
is extremely low (3%). It is even a greater challenge to use this method for the preparation
of 2-(2,6-disubstituted cyclohexenylidene) malonic acid derivatives using sterically
more hindered 2,6-disubstituted cyclohexenone as the raw material.
[0004] In the second method, a cyclohexadiene cobalt complex is used as a starting material
for preparing the 2-(cyclohexenylidene) malonic acid derivative (
Organometallics 1989, 8(10), 2474). The cyclohexadiene cobalt complex reacts with dimethyl malonate at -78°C in the
presence of a strong base LDA to produce dimethyl 2-(cyclohexenylidene) malonate.
This reaction can afford the target product in moderate yield; however, large amount
of metallic reagents and ultra-low temperature operation are required, causing high
cost, high pollution of this method, making it not suitable for industrial production.
[0005] Because of the scarcity of efficient method for the synthesis of 2-(cyclohexenylidene)
malonic acid derivative with multiple functional groups, the applications of this
class of compound in organic synthesis especially in pharmaceutical preparation are
extremely limited.
[0006] The first object of the present invention is to provide an efficient method for synthesizing
2-(cyclohexenylidene) malonic acid derivatives, particularly the sterically more hindered
2-(2,6-disubstituted cyclohexenylidene) malonic acid derivatives.
[0007] The second object of the present invention is to provide a use of 2-(cyclohexenylidene)
malonic acid derivatives, particularly the sterically more hindered 2-(2,6-disubstituted
cyclohexenylidene) malonic acid derivative, in the organic synthesis.
[0008] The inventors of the present invention, through numerous research and exploration,
have successfully developed a method for preparing 2-(cyclohexenylidene) malonic acid
derivatives, particularly 2-(2,6-disubstituted cyclohexenylidene) malonic acid derivatives.
Meanwhile, the inventors of the present invention, through further research, have
successfully applied this method and the intermediates to the synthesis of 2-aryl
malonic acid derivatives and their corresponding drugs such as Pinoxaden (CAS 243973-20-8).
SUMMARY
[0009] The first object of the present invention is to provide a new method for synthesizing
2-(cyclohexenylidene) malonic acid derivatives in which an olefin (1) is used as starting
material. This method comprises the step of: cyclizing compound (1) with compound
(2) in the presence of catalyst A to give the 2-(cyclohexenylidene) malonic acid derivative
(4) via intermediate (3), as shown in the following reaction scheme:

wherein:
R1, R2, R3, R4 and R5 each are independently hydrogen, a C1-C10 alkyl group, a C6-C12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen,
oxygen and sulfur; and
X1 and X2 each are independently a cyano group or -COR6 where R6 is selected from hydrogen, a C1-C10 alkyl group, a C1-C10 alkoxy group, a C6-C12 aryloxy group, a C1-C10 alkylamino group, a C6-C12 arylamino group, a di(Ci-Cio alkyl) amino group, a (C1-C10 alkyl)(C6-C12 aryl) amino group, a di(C6-C12 aryl) amino group, a C6-C12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen,
oxygen and sulfur.
[0010] The inventors of the present invention have also found that compound (1) and compound
(2) may undergo cyclization reaction in the presence of the catalyst A, to produce
the 2-(cyclohexenylidene) malonic acid derivative (4) directly in a "one-pot" method
without separation of the intermediate (3), as shown in the following reaction scheme:

wherein:
R1, R2, R3, R4 and R5 each are independently hydrogen, a C1-C10 alkyl group, a C6-C12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen,
oxygen and sulfur; and
X1 and X2 each are independently a cyano group or -COR6 where R6 is selected from hydrogen, a C1-C10 alkyl group, a C1-C10 alkoxy group, a C6-C12aryloxy group, a C1-C10 alkylamino group, a C6-C12 arylamino group, a di(C1-C10 alkyl) amino group, a (C1-C10 alkyl)(C6-C12 aryl) amino group, a di(C6-C12 aryl) amino group, a C6-C12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen,
oxygen and sulfur.
[0011] A molar ratio of compound (1) to compound (2) is 0.8-2.0:1, preferably, 1.0-1.5:1.
[0012] The catalyst A used for the cyclization reaction may be an organic acid, including
but not limited to acetic acid, propionic acid and TsOH; an organic base, including
but not limited to Et
3N, DABCO, TBU, pyrrolidine and piperidine; an inorganic base, including but not limited
to potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide and
sodium hydride; or a mixture thereof; preferably, Et
3N and DABCO.
[0013] A molar ratio of the catalyst A to compound (2) is 0.005-2.4:1, preferably 0.1-1.0:1.
[0014] A solvent for the cyclization reaction is selected from water, an organic solvent,
or a mixture thereof. The organic solvent may be an aromatic hydrocarbon such as benzene,
toluene and chlorobenzene, an alcohol such as methanol and ethanol, an ether such
as diethyl ether and tetrahydrofuran, a nitrile such as acetonitrile, an ester such
as ethyl acetate, an amide such as N,N-dimethylformamide, or a sulfone/sulfoxide such
as dimethyl sulfoxide; preferably, toluene.
[0015] The cyclization reaction may be carried out in the absence of a solvent.
[0016] A temperature of the cyclization reaction is 0-150°C, preferably 80-130°C.
[0017] The second object of the present invention is to provide a method for preparing 2-aryl
malonic acid derivatives from the 2-(cyclohexenylidene) malonic acid derivatives,
comprising: aromatizing compound (4) in the presence of catalyst B to give a 2-aryl
malonic acid derivative (5), as shown in the following reaction scheme:

wherein:
R1, R2, R3, R4 and R5 each are independently hydrogen, a C1-C10 alkyl group, a C6-C12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen,
oxygen and sulfur; and
X1 and X2 each are independently a cyano group or -COR6 where R6 is selected from hydrogen, a C1-C10 alkyl group, a C1-C10 alkoxy group, a C6-C12 aryloxy group, a C1-C10 alkylamino group, a C6-C12 arylamino group, a di(C1-C10 alkyl) amino group, a (C1-C10 alkyl)(C6-C12 aryl) amino group, a di(C6-C12 aryl) amino group, a C6-C12 aryl group or a heteroaryl group containing one or two atoms selected from nitrogen,
oxygen and sulfur.
[0018] The catalyst B is a metal catalyst, preferably Pd/C. A temperature of the aromatization
reaction is 100-400°C, preferably 180-220°C. The aromatization reaction is carried
out in the absence of a solvent or in the presence of a solvent selected from an alcohol,
an ether, an ester, an amide or an aromatic hydrocarbon having a boiling point higher
than 150°C.
[0019] The present invention provides a new method for preparing the 2-(cyclohexenylidene)
malonic acid derivative and uses thereof. This method employs a completely different
synthetic strategy from the technologies known in the prior arts, where the technologies
known in the prior art all use raw materials with cyclohexane skeleton to produce
the 2-(cyclohexenylidene) malonic acid derivatives; whereas, the present invention
uses non-cyclohexane skeleton-based raw materials for the preparation of the 2-(cyclohexenylidene)
malonic acid derivatives. Furthermore, this method has particularly the following
advantages: (1) the method can be very efficiently used for the synthesis of highly
sterically-hindered target products, such as 2-(2,6-disubstituted cyclohexenylidene)
malonic acid derivatives; (2) the reaction yield is high, the reaction conditions
are mild, and the wastes are less, favorable for industrial production. More importantly,
the present invention extends the further use of 2-(cyclohexenylidene) malonic acid
derivatives in organic synthesis, especially in the synthesis of 2-aryl malonic acid
derivatives and their corresponding drugs such as Pinoxaden.
DETAILED DESCRIPTION OF EMBODIMENTS
[0020] Some features of the invention will be further illustrated with reference to the
following embodiments, but the embodiments are not intended to limit the scope of
the invention.
Preparation of 2-(4-heptylidene) malononitrile
[0022] To a reaction flask were sequentially added 65.0 g of 4-heptanone (0.569 mol), 39.4
g of malononitrile (0.569 mol), 6.6 g of ammonium acetate (0.086 mol), 10.3 g of acetic
acid (0.171 mol) and toluene. The reaction mixture was refluxed, and the resulted
water was removed. After the reaction was complete, the reaction mixture was cooled,
washed with water, concentrated and purified to give 84.9 g of 2-(4-heptylidene) malononitrile,
and the yield was 92%.
1H NMR (CDCl
3, 500 MHz, TMS): δ 2.57-2.53 (m, 4H), 1.64-1.60 (m, 4H), 1.02 (t, J = 7.5 Hz, 6H).
13C NMR (CDCl
3, 125 MHz): δ 186.08, 111.88, 85.91, 37.47, 21.44, 12.81.
Preparation of 2-(1-(4-methoxyphenyl)-2-propylidene) malononitrile
[0023] To a reaction flask were sequentially added 82.1 g of 1-(4-methoxyphenyl) -2-propanone
(0.50 mol), 33.0 g of malononitrile (0.50 mol), 5.8 g of ammonium acetate (0.075 mol),
9.0 g of acetic acid (0.15 mol) and toluene. The reaction mixture was refluxed, and
the resulted water was removed. After the reaction was complete, the reaction mixture
was cooled, washed with water, concentrated and purified to give 100.8 g of 2-(1-(4-methoxyphenyl)-2-propylidene)
malononitrile, and the yield was 95%.
1H NMR (CDCl
3, 500MHz, TMS): δ 7.12 (d, J = 11 Hz, 2H), 6.88 (d, J = 11 Hz, 2H), 3.80 (s, 5H),
2.17 (s, 3H).
13C NMR (CDCl
3, 125 MHz): δ 180.2, 159.2, 129.9, 126.1, 114.5, 112.0, 111.7, 85.6, 55.2, 42.6, 22.0.
Example 1 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile
[0024] 24.3 g of 2-(4-Heptylidene) malononitrile (0.15 mol), 10.5 g of 2-methylpropenal
(0.15 mol) and 15.2 g of triethylamine (0.15 mol) were sequentially added to toluene.
The reaction mixture was refluxed until the reaction was complete. Then, the reaction
mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated
and purified to give 25.7 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile,
and the yield was 80%.
1H NMR (CDCl
3, 500MHz, TMS): δ6.14-6.14 (m, 1H), 3.08-3.04 (m, 1H), 2.82-2.75 (m, 1H), 2.57-2.46
(m, 2H), 2.04-2.01 (m, 1H), 1.56-1.51 (m, 2H), 1.48-1.41 (m, 1H), 1.12-1.01 (m, 6H),
1.00-0.98 (m, 3H).
13C NMR (CDCl
3, 125MHz): δ 175.12, 148.74, 134.78, 113.99, 113.74, 43.75, 34.75, 28.13, 16.55, 15.52,
20.91, 13.59, 11.98.
Example 2 Preparation of mixture of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)
malononitrile and 2-(2,6-diethyl-4-methyl-3-ene-1-cyclohexylidene) malononitrile
[0025] 25.0 g of 2-(4-Heptylidene) malononitrile (0.154 mol), 14.0 g of 2-methylpropenal
(0.200 mol) and 15.6 g of triethylamine (0.154 mol) were sequentially added to toluene.
The reaction mixture was refluxed until the reaction was complete. Then,the reaction
mixture was cooled, washed with 1 N diluted hydrochloric acid, dried and concentrated
to give 30.4 g of the mixture of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)
malononitrile and 2-(2,6-diethyl-4-methyl-3-ene-1-cyclohexylidene) malononitrile in
a ratio of 91:9 by GC-MS analysis.
Example 3 Preparation of 2-(2,6-diethyl-3-hydroxy-4-methyl-1-cyclohexyliene) malononitrile
[0026] 3.2 g of 2-(4-Heptylidene) malononitrile (0.02 mol), 1.4 g of 2-methylpropenal (0.02
mol) and 2.0 g of triethylamine (0.02 mol) were sequentially added to toluene to react
at 50°C for 5 h. Then the reaction mixture was cooled, washed with 1 N diluted hydrochloric
acid, dried, concentrated and purified to give 4.4 g of 2-(2,6-diethyl-3-hydroxy-4-methyl-1-cyclohexyliene)
malononitrile, and the yield was 95% yield.
1H NMR (CDCl
3, 500MHz, TMS): δ 3.82 (s, 1H), 3.11-3.08 (m, 1H), 3.03-2.99 (m, 1H), 2.06-2.05 (m,
1H), 1.87-1.81 (m, 2H), 1.73-1.65 (m, 2H), 1.62-1.52 (m, 3H), 1.08-1.02 (m, 9H).
13C NMR (CDCl
3, 125 MHz): δ 188.8, 112.2, 112.0, 87.1, 75.1, 53.1, 44.0, 30.9, 28.4, 26.4, 26.0,
17.4, 12.9.
Example 4 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile
[0027] 2.3 g of 2-(2,6-Diethyl-3-hydroxy-4-methyl-1-cyclohexyliene) malononitrile (0.01
mol) prepared in Example 3 and a solution of 1.0 g of triethylamine (0.01 mol) in
toluene were reacted under reflux. After the reaction was complete, the reaction mixture
was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated and purified
to give 1.8 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile, and
the yield was 84%.
Example 5 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile
[0028] 32.4 g of 2-(4-Heptylidene) malononitrile (0.20 mol), 14.0 g of 2-methylpropenal
(0.20 mol) and 2.2 g of triethylenediamine (0.02 mol) were sequentially added to toluene
to react at 130°C. After the reaction was complete, the reaction mixture was cooled,
washed with 1 N diluted hydrochloric acid, extracted with ethyl acetate, dried, concentrated
and purified to give 39.4 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile,
and the yield was 92%.
Example 6 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile
[0029] A solution of 48.7 g of 2-(4-heptylidene) malononitrile (0.30 mol) in THF was dropwise
added to a solution of 12.4 g of NaH (0.31 mol) in THF at 0-5°C. After addition, the
mixture was warmed to room temperature and then reacted for 20 min. Then a solution
of 27.3 g of 2-methylpropenal (0.39 mol) in THF was dropwise added. The reaction mixture
was heated and then refluxed until the reaction was complete. The reaction mixture
was cooled, quenched with 1 N diluted hydrochloric acid, extracted with ethyl acetate,
dried, concentrated and purified to give 13.5 g of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)
malononitrile.
Example 7 Preparation of 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile
[0030] To a reaction flask were sequentially added 25.0 g of 2-(4-heptylidene) malononitrile
(0.154 mol), 14.0 of 2-methylpropenal (0.20 mol) and 3.4 g of triethylenediamine (0.031
mol). The reaction mixture was reacted at 80°C. After the reaction was complete, the
reaction mixture was cooled, dissolved in ethyl acetate, washed with 1 N diluted hydrochloric
acid, dried and concentrated by distillation to give 21.4 g of the target product.
Example 8 Preparation of mixture of 2-(2,6-diethyl-5-phenyl-2-ene -1-cyclohexylidene)
malononitrile and 2-(2,6-diethyl-5-phenyl-3-ene-1-cyclohexylidene) malononitrile
[0031] 64.9 g of 2-(4-Heptylidene) malononitrile (0.40 mol), 68.7 g of cinnamaldehyde (0.52
mol) and 40.5 g of triethylamine (0.40 mol) were sequentially added to toluene. The
reaction mixture was refluxed until the reaction was complete. Then, the reaction
mixture was cooled, washed with 1 N diluted hydrochloric acid, dried and concentrated
to give 83.4 g of the mixture of 2-(2,6-diethyl-5-phenyl -2-ene-1-cyclohexylidene)
malononitrile and 2-(2,6-diethyl-5-phenyl-3-ene-1-cyclohexylidene) malononitrile in
a ratio of 94:6 by GC-MS analysis. The resulting mixture was further purified to give
77.4 g of 2-(2,6-diethyl-5-phenyl -2-ene-1-cyclohexylidene) malononitrile, and the
yield was 70%.
1H NMR (CDCl
3, 500MHz, TMS): δ 7.31-7.28 (m, 2H), 7.26-7.23 (m, 1H), 7.08-7.06 (m, 2H), 6.36-6.25
(m, 1H), 3.31 (d, 1H, J = 5.0 Hz), 3.21-3.18 (m, 1H), 2.86-2.77 (m, 2H), 2.67 (dd,
1H, J
1 = 20.5 Hz, J2 = 4.0 Hz), 2.59-2.51 (m, 1H), 1.77-1.70 (m, 1H), 1.65-1.59 (m, 1H),
1.12 (t, 3H, J = 7.5 Hz), 1.05 (t, 3H, J = 7.5 Hz).
13C NMR (CDCl
3, 125 MHz): δ 173.0, 142.4, 139.7, 136.7, 128.7, 127.0, 126.5, 113.3, 81.0, 51.5,
41.7, 28.0, 27.6, 26.7, 13.5, 12.1.
Example 9 Preparation of 2-(6-(4-methoxyphenyl)-4-methyl-2-ene-1-cyclohexylidene)malononitrile
[0032] 31.8g of 2-(1-(4-Methoxyphenyl)-2-propylidene) malononitrile (0.15mol), 14.0 g of
2-methylpropenal (0.20 mol) and 15.2 g of triethylamine (0.15 mol) were sequentially
added to toluene. The reaction mixture was refluxed until the reaction was complete.
Then, the reaction mixture was cooled, washed with 1 N diluted hydrochloric acid,
dried, concentrated and purified to give 34.9 g of 2-(6-(4 -methoxyphenyl)-4-methyl-2-ene-1-cyclohexylidene)
malononitrile, and the yield was 93%.
1H NMR (CDCl
3, 500MHz, TMS): δ 9.02-7.00 (m, 2H), 6.94 (dd, J
1 = 10.0 Hz, J2 = 2.5 Hz, 1H), 6.85-6.84 (m, 2H), 6.67 (d, J = 10.0 Hz, 1H), 4.27-4.25
(m, 1H), 3.78 (s, 3H), 2.39-2.31 (m, 1H), 2.08-2.04 (m, 1H), 1.76-1.71 (m, 1H), 1.10
(d, J = 7.5 Hz, 3H).
13C NMR (CDCl
3, 125 MHz): δ 170.7, 158.8, 155.3, 130.4, 130.3, 128.1, 124.5, 114.3, 114.1, 112.2,
111.9, 82.1, 55.2, 43.4, 37.7, 27.5, 19.9.
Example 10 Preparation of 2-(2,6-diphenyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile
[0033] 77.5 g of 2-(2,6-Diphenylpropylidene) malononitrile (0.30 mol), 23.1 g of 2-methylpropenal
(0.33 mol) and 30.3 g of triethylamine (0.30 mol) were sequentially added to toluene.
The reaction mixture was refluxed until the reaction was complete. Then, the reaction
mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated
and purified to give 91.2 g of 2-(2,6-diphenyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile,
and the yield was 98%.
1H NMR (CDCl
3, 500MHz, TMS): δ 7.46-7.24 (m, 1H), 6.38-6.37 (m, 1H), 4.54-4.52 (m, 1H), 2.57-2.51
(m, 1H), 2.36-2.30 (m, 1H), 1.95-1.88 (m, 1H), 1.17 (d, J = 9.0 Hz, 3H).
13C NMR (CDCl
3, 125MHz): δ 169.9, 153.1, 138.4, 137.8, 137.4, 129.1, 129.0, 128.8, 127.6, 127.0,
113.6, 110.9, 83.9, 45.9, 37.2, 28.5, 20.4.
Example 11 Preparation of 2-(3-methyl-2-ene-1-cyclohexylidene) malononitrile
[0034] 26.5 g of 2-(2-Propylidene) malononitrile (0.25 mol), 22.8 g of vinyl methyl ketone
(0.32 mol) and 25.2 g of triethylamine (0.25 mol) were sequentially added to toluene.
The reaction mixture was refluxed until the reaction was complete. Then, the reaction
mixture was cooled, washed with 1 N diluted hydrochloric acid, dried, concentrated
and purified to give 26.1 g of 2-(3-methyl-2-ene-1-cyclohexylidene) malononitrile.
1H NMR (CDCl
3, 500MHz, TMS): δ6.61-6.61 (m, 1H), 2.72 (t, J = 6.5 Hz, 2H), 2.34 (t, J = 7.5 Hz,
2H), 2.07-2.07 (m, 3H), 1.91-1.85 (m, 2H).
13C NMR (CDCl
3, 125 MHz): δ 170.7, 162.1, 121.5, 113.0, 112.3, 31.1, 28.9, 25.2, 21.2.
Example 12 Preparation of methyl 2-cyano-2-(2,6-diethyl-4-methyl-1-cyclohexenylidene)acetate
[0035] 58.6 g of Methyl 2-cyano-3-propyl-2-hexenoate (0.300 mol), 27.3 g of 2-methylpropenal
(0.390 mol) and 30.3 g of triethylamine (0.300 mol) were sequentially added to toluene.
The reaction mixture was refluxed until the reaction was complete. Then, the reaction
mixture was cooled, washed with 1 N diluted hydrochloric acid, dried and concentrated
to give 62.8 g of methyl 2-cyano-2-(2,6-diethyl-4-methyl-1-cyclohexenylidene) acetate,
and the yield was 84%.
1H NMR (CDCl
3, 500MHz, TMS): δ 6.02-5.90 (m, 1H), 3.83-3.82 (m, 3H), 3.63-3.07 (m, 1H), 2.91-2.44
(m, 2H), 2.22-1.95 (m, 2H), 1.58-1.42 (m, 3H), 1.08-1.04 (m, 4H), 1.00-0.90 (m, 5H).
Example 13 Preparation of diethyl 2-(3-methyl-2-ene-1-cyclohexylidene)malonate
[0036] 120.1 g of Diethyl 2-(2-propylidene) malonate (0.60 mol), 54.7 g of vinyl methyl
ketone (0.78 mol) and 60.6 g of triethylamine (0.60 mol) were sequentially added to
toluene. The reaction mixture was refluxed until the reaction was complete. Then,
the reaction mixture was cooled, washed with IN diluted hydrochloric acid, dried and
concentrated by distillation to give 60.5 g of diethyl 2-(3-methyl-2-ene-1-cyclohexylidene)malonate.
1H NMR (CDCl
3, 500MHz, TMS): δ6.61-6.60 (m, 1H), 4.28-4.18 (m, 4H), 2.65 (t, J = 8.0 Hz, 2H), 2.15
(t, J = 8.0 Hz, 2H), 1. 898 (d, J = 1.5 Hz, 1H), 1.80-1.73 (m, 2H), 1.32-1.26 (m,
6H).
13C NMR (CDCl
3, 125 MHz): δ 165.8, 165.8, 151.9, 151.6, 121.4, 118.7, 60.6, 60.4, 30.6, 27.1, 24.8,
21.8, 13.9.
Example 14 Preparation of 2-(2,6-diethyl-4-methylphenyl) malononitrile
[0037] 214.1 g of 2-(2,6-Diethyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile (1 mol)
and 2.2 g of Pd/C were heated to 180°C under a nitrogen atmosphere. After the reaction
was complete, the reaction mixture was cooled, and ethyl acetate was added. The mixture
was filtered to remove the catalyst (Pd/C). A small amount of solvent was used to
wash the catalyst. The organic phase was dried and crystallized by concentration to
give 188.9 g of 2-(2,6-diethyl-4-methylphenyl) malononitrile, and the yield was 89%.
Example 15 Preparation of 2-(2,6-diphenyl-4-methylphenyl) malononitrile
[0038] 15.5 g of 2-(2,6-Diphenyl-4-methyl-2-ene-1-cyclohexylidene) malononitrile (0.05 mol)
and 0.8 g of Pd/C was heated to 220°C. After the reaction was complete, the reaction
mixture was cooled and filtered to remove the catalyst (Pd/C). A small amount of solvent
was used to wash the catalyst. The organic phase was concentrated to give 10.9 g of
2-(2,6-diphenyl-4-methylphenyl) malononitrile, and the yield was 71%.
1H NMR (CDCl
3, 500MHz, TMS): δ 7.54-7.46 (m, 10H), 7.21 (s, 2H), 5.11 (s, 1H), 2.44 (s, 3H).
13C NMR (CDCl
3, 125 MHz): δ 143.4, 140.2, 138.8, 131.6, 129.4, 129.0, 128.7, 119.7, 112.2, 24.4,
21.0.
Example 16 Preparation of diethyl 2-(3-methylphenyl)malonate
[0039] 20.0 g of Diethyl 2-(3-methyl-2-ene-1-cyclohexylidene) malonate (0.08 mol) and 0.04
g of Pt/C were heated to 160°Cin N,N-dimethylacetamide. After the reaction was complete,
the reaction mixture was cooled and filtered to remove the catalyst (Pt/C). A small
amount of solvent was used to wash the catalyst. The organic phase was concentrated
to give 16.6 g of diethyl 2-(3-methylphenyl) malonate, and the yield was 84%.
1H NMR (CDCl
3, 500MHz, TMS): δ 7.27-7.13 (m, 4H), 4.57 (s, 1H), 4.20 (q,
J = 7.0 Hz, 4H), 2.35 (s, 3H), 1.26 (t, J = 7.0 Hz, 6H).
13C NMR (CDCl
3, 125 MHz): δ 168.2, 138.2, 132.6, 129.8, 128.9, 128.4, 126.2, 61.7, 57.8, 14.0, 13.9.
Example 17 Preparation of dimethyl 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene)malonate
[0040] To a reaction flask were sequentially added with 22.8 g of dimethyl 2-(4-heptylidene)
malonate (0.10 mol), 7.0 g of 2-methylpropenal (0.10 mol) and 2.2 g of triethylenediamine
(0.02 mol) to react by heating. After the reaction was complete, the reaction mixture
was cooled, dissolved with ethyl acetate, washed with IN diluted hydrochloric acid,
dried and concentrated to give dimethyl 2-(2,6-diethyl- 4-methyl-2-ene-1-cyclohexylidene)
malonate.
Example 18 Preparation of dimethyl 2-(2,6-diethyl-4-methylphenyl) malonate
[0041] Dimethyl 2-(2,6-diethyl-4-methyl-2-ene-1-cyclohexylidene) malonate prepared in Example
17 and 1.1 g of Pd/C were heated to 180°C under a nitrogen atmosphere. After the reaction
was complete, the reaction mixture was cooled, and ethyl acetate was added. The mixture
was filtered to remove the solid. The organic phase was dried and concentrated to
give 22.2 g of dimethyl 2-(2,6-diethyl-4-methylphenyl) malonate, and the yield was
80%.
1H NMR (CDCl
3, 500MHz, TMS): δ 6.93 (s, 2H), 5.06 (s, 1H), 3.73 (s, 6H), 2.64 (q, J = 7.0 Hz, 4H),
2.30 (s, 3H), 1.18 (t,
J = 7.0 Hz, 6H).
13C NMR (CDCl
3, 125 MHz): δ 15.2, 21.1, 26.6, 51.5, 52.6, 126.4, 127.9, 137.9, 143.6, 169.3.
Example 19 Preparation of pinoxaden
[0042] 15.3 g of Dimethyl 2-(2,6-diethyl-4-methylphenyl) malonate prepared in Example 18
(0.05 mol), 10.5 g of hexahydro-1,4,5-oxadiazepine dihydrochloride (0.06 mol) and
20.2 g of triethylamine (0.20 mol) were stirred to react in xylene under refluxing
temperature. After the reaction was complete, the reaction mixture was cooled. 10.8
g of Pivaloyl chloride (0.09 mol) was added. The mixture was reacted at room temperature.
After the reaction was complete, the reaction mixture was adjusted to be acidic with
dilute hydrochloric acid and then extracted with ethyl acetate. The organic phases
were combined, dried and crystallized by concentration to give 14.4 g of Pinoxaden,
and the yield was 72%.
1H NMR (CDCl
3, 500MHz, TMS): δ8.88 (s, 2H), 4.28-4.26 (m, 2H), 3.94-3.93 (m, 2H), 3.89-3.83 (m,
4H), 2.56-2.47 (m, 2H), 2.45-2.40 (m, 2H), 2.39 (s, 3H), 1.12 (t, J = 9.0 Hz, 3H),
1.23 (s, 9H).